fluorine in medicinal chemistry - semantic...

Fluorine in Medicinal

Chemistry

Steve Swallow

Historical Perspective

2

• Early use dominated by steroids & anesthetics

• 80’s surge following development of DAST in 1970

0

10

20

30

40

50

60

1950-60 1961-70 1971-80 1981-90 1991-00 2001-10 2011-13

co

un

t

decade

Henri

Moissan

~15% of marketed drugs contain at least one fluorine

Diversity of Fluorine Containing Pharmaceuticals

3

ArF

AlkF

ArCF3

HetArF

HetArCF3

AlkCF3

OCHF2

SCH2F SCH2CF3

OCH2CF3

COCF3

NHCH2CF3

AlkF2

SCHF2

OCF3

OCF2

47%

18%

15%

The use of fluorine is still dominated by a few chemotypes

See also J. Chem.

Ed.

2013, 90, 1403

Fluorinated AstraZeneca Pharmaceuticals

4

NH

N

NO

O

Cl

F

N

O

F

F

NH

N

NN

NN

O

OHOHOH

S

F

NS

ON

N O

OHOHO

OH

NH

O

CF3 N

OHS

O

O

F

S CF2CF

3

O

OH

OH

H

H H

The Special Nature of Fluorine

5

H C N O F Cl Br

Van de Waals radius 1.2 1.7 1.55 1.52 1.47 1.75 1.85

Electronegativity 2.1 2.5 3 3.5 4 3.2 2.8

Bond strength to C 98 83 70 84 105 77 66

Uniquely, incorporation of fluorine introduces polar hydrophobicity

F as a substituent is:

• Small

• Low MW = 19

• Highly electronegative

• Very strong

• Highly polarised

• Has low energy s*

The C-F bond is :

FC d+ d-

Influences of Fluorine in Medicinal Chemistry

6

• Powerful inductive electronic effects

• Electrostatic molecular interactions

F pKa

Metabolic

oxidation

potential

Conformational

effects

Molecular

recognition

Lipophilicity

F can influence potency, selectivity, absorption & metabolism

Impact of Fluorination on Lipophilicity

7

H X

X sI

H 0.00 0.00

F 0.14 0.52

Cl 0.71 0.47

CH3 0.56 0.04

CF3 0.88 0.42

OCH3 -0.02 0.29

OCF3 1.04 0.39

SO2CH3 -1.63 0.48

SO2CF3 0.55 0.73

• Strong EWG & modest increase in logP

• Low risk, potentially high impact modification o metabolic stability

o potency

• Strong EWG & significant increase in logP

Ar-F

Ar-CF3

Ar-SO2CF3

• Powerful EWG & large increase in logP

• 150x more lipophilic than SO2Me!

8

N

NN

N

ONH2

CF3

F

F

F

N

NN

N

ONH2

F

F

F

Clp (ml/min/kg)

T1/2 (h)

F

70 1.7 2%

Clp (ml/min/kg)

T1/2 (h)

F

60 1.7 76%

permeability

Impact of Fluorination on logD & Permeability

DPPIV inhibitors – Sitagliptin (JANUVIA™)

• Triazoles are excellent H-bond

acceptors, strong dipole across

heterocycle

J. Med. Chem. 2005, 48, 141

Bioorg. Med. Chem. Lett. 2007, 17, 3373

• Improved absorption and

bioavailability

X

CH2CH3 1.02

CF3 0.88

9

permeability

Impact of Fluorination on LogD & Permeability

CCR5 antagonists - AstraZeneca

R

NF

F

N

N

N

R

NF

F

N

N

N

F

F

Significant influence of F on heterocycle properties

Clp (ml/min/kg)

T1/2 (h)

F

16 3.9 9%

LogD

1.8

Clp (ml/min/kg)

T1/2 (h)

F

6 3.9 68%

LogD

2.5

10

N

NN

N

ONH2

CF3

F

F

F

N

NN

N

ONH2

F

F

F

permeability potency

Impact of Fluorination on Permeability

DPPIV inhibitors – Sitagliptin (JANUVIA™)

CV safety

• Triazoles are excellent H-bond

acceptors, strong dipole across

heterocycle

J. Med. Chem. 2005, 48, 141


• Improved absorption and

bioavailability

Clp (ml/min/kg)

T1/2 (h)

F

16 3.9 9%

LogD

1.8

Clp (ml/min/kg)

T1/2 (h)

F

6 3.9 68%

LogD

2.5


11

ChemBioChem 2004, 5, 637

Impacts on pKa

Additional effects

on partitionining

at pH 7.4

O

F

F O

OH

F

FO

R

OR

F

RF

OH

Increase in LogD not always true for F addition

DlogD for

exchange of

H to F

http://onlinelibrary.wiley.com/doi/10.1002/cbic.200301023/full

12

O

F

F O

OH

F

FO

R

OR

F

RF

OH

Lo

gD

ROCH2CH3 ROCH2CH2F


Increase in LogD not always true for F addition

13


NH

F

F

NH

F

NH

F

F

NH

O

OH

NH

F

F

logD 4.6

logD

4.1

3.7

4.0

D -0.5

D -0.9

D -0.6


N

NH

R

NN

O

NH

NH

FF

R = logD

NH

4.1 NH

F 3.3

R = logD

NH

3.5 2.8 NH

F

NH

3.1 2.5 NH

F D -0.6

D -0.7

D -0.8


Aliphatic F addition can lead to reduced logD

Acids - Carbonic anhydrase II inhibitors

14

Impact of Fluorination on pKa

S

O

O

NH2

S

O

O

F

F

F NH2

J. Biol. Chem. 1993, 15, 26233

pKa 10.5 pKa 5.8

Ki = 320mM Ki = 2nM

1bcd

S

O

RO

NH2

CF3

C4F9

C2F5

CCl3

CHF2

CH2F

CH2Cl

CF3CH2

CH3

Linear Relation between Ki & pKa

F substitution is a powerful tool for pKa modulation


Bases

15

ChemMedChem. 2007, 2, 1100

CHxFyN

n DpKa

1 -1.7 / b-F

2 -0.7 / g-F

3 -0.3 / d-F

4 0.1 / e-F

n

NH2 NH

2

F NH2

F

F NH2

F

F

F

NH2

CF3 NH

2

CF3 NH

2CF

3 NH2

10.7 9.0 7.3 5.7

5.7 8.7 9.7 10.7

D -1.7 D -1.7 D -1.6

g b d

Generally predictable impact of F on basic pKa’s


Bases

16

ChemMedChem. 2007, 2, 1100

NH

11.1

More complicated in ring systems – conformational effects

NH

F

NH

FF

NH

F

9.4

9.3

8.5

7.4

NH

FF

NH

F

F

N+H

H

Axial F preferred in

protonated form

Contribution to higher

than expected pKa’s

Expect 9.1

(D = -1.7 + -0.3 = -2.0?) Expect 7.1

Fluorine substitution can give rise to conformational effects too...

Impact of Fluorine on Conformation

17

Chem. Soc. Rev. 2008, 37, 308

RR

FF

RR

HH

~111o ~116o

Geometry at carbon

OP

O

O

O

R - -

Better mimic

OP

O

O

R

FF

-

- OP

O

O

R

HH

-

-

Dipole interactions

N

O

H

H

F

H H

N

O

H H

HF

H

Charge-Dipole interactions

NH

H

FH

NH

HH

F

+ +

d- d-

F

HH

s*

O

F

s*

n

Hyperconjugation & s* C-F Other:

1,2 C-F bond attraction

1,3 C-F bond repulsion

Example Cathepsin K inhibitors - Odanacatib

18

Chem. Eur. J., 2003, 9, 4510 Zanda

NH

O

NH

CN

CF3

F

MeSO2

Metabolism

blocked

R

NH

O

NH

CN

CF3

Non-basic

amine

H-bond

maintained

hydroxylation

• 10-20x > potency

• Improved amide stability

• Short t1/2 in cyno

R

NH

O

O

NH

CN

H-bond

required

solvent

• Peptidic nature • Improved metabolism

• Good selectivity

Odanacatib

Bioorg. Med. Chem. Lett., 2008, 18, 923


Amine can be rendered non-basic by Fluorine substitution


Example – 5HT2A antagonists

19

J Med Chem. 2001, 44,1603

NH

NH

• Poor F% • Ki = 0.99nM

pKa 10.4

hydroxylation

NH

NH

F

pKa 8.5

• F = 18% • Ki = 0.43nM

NH

NH

F

F

• F = 80% • Ki = 0.06nM ~10x

(Note Cl = 2.3nM)

Metabolism

blocked

Absorption improved by pKa modulation with fluorine

Intermolecular Interactions in Proteins

20

Science, 2007, 317, 1881

• Observed interactions reflect that F not a good H-bond acceptor

- But: C-F dipole undergoes ‘multipolar interactions’ – to amide N-H,

backbone C=O, C-H and guainidinium groups

- Can provide some potency benefit beyond lipophilicity

Dipole (δ+/δ-)...Dipole (δ+/ δ-)

J. Med. Chem. 2011, 54, 2255

Specific interactions dominated by dipole-dipole interactions

3FLN


Example - KSP inhibitors

21


N

N O

FF

NH2

• MDR efflux ratio = 1000 • MDR efflux ratio = 3

pKa 10.3 pKa 7.0

Reduced

efflux Cellular

Efflux N

N O

FF

NH2

F

F

Cellular efflux improved by pKa modulation with fluorine

Caution in use of Fluoroethyl Amines & Ethers

J. Med. Chem. 2008, 51, 4239

Metabolism to toxic metabolites

22

N

OH

N O

N

F

FF

“we were surprised to

find mortality within 12 h

postdose in 2 of 3 rats in

the 12 mg/kg group.”

N

OH

N O

N

FF

pKa 8.8

Desire to

reduce pKa to

reduce efflux

pKa 7.6

Reflects AZ experience.

Consequence of increase

focus on desirable

physchem space?

N

OH

N O

N

FF

F

pKa 7.6


• Fluoroacetic acid is a known potent rodenticide and human toxin

- Lethal in man in 2-10mg/kg doses

- Dogs also particularly sensitive: LD50 0.05-1mg kg

- Mechanism well understood – inhibitor of tricarboxylic acid cycle

• Described in Stryer in 1980’s


23

FO

OHF

O

OH

OHO

OH

OOHO

OH

OOH

OH

OH

O

2-fluorocitrate 4-hydroxy-trans-aconitatepotent inhibitor of aconitase


• Fluoroacetic acid is a known potent rodenticide and human toxin

- Lethal in man in 2-10mg/kg doses

- Dogs also particularly sensitive: LD50 0.05-1mg kg

- Mechanism well understood – inhibitor of tricarboxylic acid cycle

• Described in Stryer in 1980’s


24

FO

OHF

O

OH

OHO

OH

OOHO

OH

OOH

OH

OH

O

2-fluorocitrate 4-hydroxy-trans-aconitatepotent inhibitor of aconitase


• Beware related compounds

1,3-difluoroacetone

25 Steve Swallow| 7th December 2011 R&D| Innovative Medicines| Global Safety Assessment

Metabolite has predictable dose dependent toxicity – extent of

metabolism unpredictable

F F

OH

F

SCoA

O

F F

O

J. Med. Chem. 2014 asap

N N

S

O

O

NH

F

F

OF

F

CN

Pesticide

Gliftor

J. Biochem. Mol. Tox. 2001, 15, 47

26

O

H

R

Fe3+

R

O

Fe4+

R

OH

H

R

O

H H

R

OH

a

b

+

Fluorination to Reduce Metabolic Oxidation

Metabolic oxidation – a complex multistep process

• Appropriate F substitution can reduce intermediate carbocation stability via

o Induction

o Lack of resonance stabilisation.

• May see oxidation switch to other positions & sites

O

F

R

Fe3+

O

F

R

Fe3+

+

+

Aromatic ring oxidation

Aromatic F to reduce metabolism or prevent bioactivation


Example- Ezetimibe (ZETIA™)

27

NO

OMe

OMe

hydroxylation

hydroxylation

demethylation

• Clinical proof of concept - modest effect

• Complex metabolite profile o Retain positive metabolite features

o Blocked undesirable oxidations

NO

OH

F

F

OH

Metabolism blocked

Ezetimibe (ZETIA™) SCH 48461

• 50x potency increase in in-vivo

efficacy model

Targeted use of Aromatic F to reduce metabolism

28

NH

N

NO

O

hydroxylation

hydroxylation

• Short half-life lead < 1hr

NH

N

NO

O

Cl

F

N

O

Metabolism

blocked Solubilizing

group

• High blood levels for 24h (po)


Example - Gefitinib (IRESSA™)




Molecular Matched Pairs – HLM Clint

29

X n DLogClint

(mean) F(0.5) DLogDa

4-F 497 0.06 0.086 0.18

4-CF3 109 0.04 0.176 0.79

4-OCF3 40 0.16 0.244 0.76

4-Me 181 -0.24 0.029 0.41

4-OCH3 299 -0.10 0.073 0.03

4-Cl 337 0.01 0.079 0.57

4-CN 168 0.25 0.193 -0.28

4-SO2Me 77 0.30 0.329 -1.12

Bioorg. Med. Chem. 2010, 4405

H X

Ar Ar

DLogClint = Log10Clint(Ar-H) – Log10Clint(Ar-X)

F(0.5)

??

Untargeted use of aromatic F mostly low impact on metabolism


Molecular Matched Pairs – HLM Clint

30

Bioorg. Med. Chem. 2010, 4405

H F

Ar Ar

R

N

N NH

O

SO2Me

N

R1

R = H Clint >150

R = F Clint = 5

DLogClint >1.4

AZ CCR5 antagonist project


31

NH

O

N

O

NH

O

N

O

F F

• Mechanism based

Cyp3A4 inhibitor

Fluorination to Prevent Metabolic Activation

Example - KCNQ2 potassium channel opener

J. Med. Chem. 2003, 46, 3778

hydroxylation

• No Mechanism based

Cyp3A4 inhibition

Metabolism blocked

R N+

O

O

R N

O

O

R N

O

OH

rationale rationale

or

Targeted use of aromatic F to prevent bioactivation


• HLM Clint (ml/min/kg) = 202

• CCL3 binding IC50 28nM

Aliphatic Oxidation - CCR1 antagonists

32


NH

O

OH

O

N

NNH

2NH

O

OH

O

N

NNH

2

F



hydroxylation Metabolism

blocked

Targeted use of aliphatic F to reduce metabolism




Aliphatic Oxidation - CCR1 antagonists

33


NH

O

OH

O

N

NNH

2NH

O

OH

O

N

NNH

2

F F



Metabolism

blocked

Targeted use of aliphatic F to reduce metabolism

34

O

O

N

CF3

OHCF

3

• Covalent binding

Fluorination to Prevent Metabolic Activation

Example – PDEIV inhibitors


• No covalent binding

dealkylation

oxidation

O

O

N

F

F

CF3

OHCF

3

FFMetabolism

blocked

rationale rationale

O

O

R

O

O

R

O

O

R

O

Targeted use of aliphatic F to prevent bioactivation

35

F pKa

Metabolic

oxidation

potential

Conformational

effects

Molecular

recognition

Lipophilicity

• Predictabl(ish)

• Can increase Clearance

• Beware cheap tricks

• Awareness

• Targeted use

to reduce Cl &

metabolic

activation

• Multipolar

interactions

dominate

Summary

• Pharmaceuticals

dominated by small

number of chemotypes

Easy access to fluorinated molecules & building blocks key to

exploit unique properties

fluorine in medicinal chemistry - semantic...

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